Neuropathic pain is a chronic condition characterized by both sensory deficits (mechanical and cold allodynia, thermal hyperalgesia) and mood disorders (anxiety and depression). Most drugs used to treat the painlike symptoms of this disorder have low efficacy, and their therapeutic actions are accompanied by major side effects. Thus, there is a pressing need for the development of more efficacious and better tolerated medications for treating chronic neuropathic pain. Tricyclic antidepressants (TCAs) and the selective, serotonin/norepinephrine reuptake inhibitors (SNRIs) contain both antiallodynic and antidepressant properties. However, they have a slow onset of action, and their chronic use is also accompanied by severe adverse effects. Understanding the cellular mechanisms mediating the actions of TCAs and SNRIs will facilitate the development of novel and more efficacious medications for the treatment of neuropathic pain. Preliminary findings from our laboratory indicate that the enzyme histone deacetylase 5 (HDAC5), which acts as a transcriptional repressor, plays a potent modulatory role in the antiallodynic and antidepressant actions of TCAs. HDAC5 modulates the function of chromatin complexes, but it is also possessing cytoplasmic functions. We will use genetic mouse models and gene transfer approaches to test our hypothesis that HDAC5 in the NAc negatively regulates the actions of TCAs and SNRIs in neuropathic pain states. In addition, we will use biochemical approaches to determine the critical HDAC5 protein-protein interactions and phosphorylation events that determine the nucleocytoplasmic shuttling of this molecule. Finally, we will use RNAsequencing to investigate the influence of HDAC5 gene in antidepressant drug induced global gene regulation in the NAc. Our findings will provide important new information on the long-term adaptations involved in the actions of antidepressant medications under neuropathic pain conditions.